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AETIOPATHOGENESIS &

ABNORMAL PRESENTATION

OF HYDATIDIFORM MOLE

Dr.Manoranjan Mahapatra,
Asst. Prof. (O&G dept.)
VSS Medical College, Burla
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Marching in right direction ------

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The critical dependent path-----

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Right initiation for embryogenesis----

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Other side of coin------

‘white currants in black currant juice’

Prune juice bleeding


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Where is the fault ????

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Salute -----------

‘Hippocrates’- 400 BC
“dropsy of uterus”

Aetius - 1600 AD
– hydatid mole
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GESTATIONAL TROPHOBLASTIC DISEASE(GTD)

• Hydatiform mole

• Invasive mole

• Choriocarcinoma

• Placental site trophoblastic tumor

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Molar Pregnancy

Background

Based on genetic and histo-pathological features.


Hydatidiform mole is subdivided into

• complete
• partial mole

• Genetic analysis by —
*Chromosomal restriction fragment length
polymorphisim analysis in molar &placental tissues
* locus
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FEATURES OF PARTIAL AND COMPLETE MOLE

Complete mole Partial mole

Fetal or embryonic tissue absent present


Hydatiform swelling of chorionic villi extensive focal
Trophoblastic hyperplasia extensive focal

Karyotype diploid Triploid


46XX (90%) (69 XXX/XXY)
46XY (10%)

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Cohn DE, Herzog TJ. Curr Opin Oncol 2000 Sep; 12(5):492-6
Complete molar pregnancy

Complete hydatidiform mole forms a multivesicular mass


with diffuse hydropic villi and a variable degree of
trophoblastic proliferation.

• no evidence of a foetus.
• This conceptus is diploid
• androgenetic in origin.

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HYDATIDIFORM MOLE
Incidence

North America and Europe:


Partial mole 1/700
Complete mole 1/1500-2000

Asian Countries:
Partial mole 1/120
Complete mole 1/350-500

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HYDATIDIFORM MOLE
Risk factors

1. Maternal age > 40 years


< 15 years

2. Paternal age > 45 years

3. Previous hydatidiform mole 1st 1-2%


2nd 15-28%

4. Vitamin A deficiency
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EXPLORATION OF CYTOGENETICS ---

• In the mouse, one can remove the paternal pronucleus


from a fertilized oocyte, and replace this by a second
maternal pronucleus, thus creating an embryo where all
chromosomes have a maternal origin
• These so called gynogenotes ( parthenogenesis) fail to
complete normal development. No extraembryonic
components are formed and the embryoblast develops
into a teratoma (Surani et al., 1984, 1986).
• In androgenotic embryos, containing paternal
chromosomes only. fail to develop an embryoblast
whereas the trophoblast proliferates excessively,
resulting in a hydatidiform mole (McGrath and Solter,
1984).
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Trophoblast vs embryoblast
• The ratio between the maternal and
paternal genomes is critical in
determining the development of both
the embryonic and extra-embryonic
tissues,

• excess of paternally derived


chromosomes leading to a complete
HM (no maternal genome) or partial
HM (lower amount of maternal
chromosomes)

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complete mole ---
Karyotype----
• 90 % - 46,XX karyotype
• 10% - 46,XY karyotype
• 46,YY has never been observed ( non-viable),

• hydatidiform mole, all mitochondria have an


exclusively maternal origin (Azuma et al.,
1991
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PARENTAL ORIGIN OF COMPLETE MOLE

• Source of diploid chromosome in c. mole---,

- Uniparental origin - all chromosomes


paternal origin
- Biparental origin

genomic imprinting plays a role in tumourigenesis

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UNIPARENTAL (ANDROGENIC)
CYTOGENETICS OF H.MOLE

Arise as a consequence of
• duplication of the haploid sperm following
fertilisation of an ‘empty’ ovum ( diandry) (Lawler
et al., 1982 ) -- ~80%
• Some complete moles arise after dispermic
fertilisation of an “empty’ ovum. (dispermy)
(Kovacs et al., 1991 ) ~ 20%

• A third possible cause, the fertilization of an empty


oocyte by a diploid sperm cell, is extremely rare
(Zaragoza et al., 2000 )

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-generation of an empty ovum
-Endoduplication of male pronecleus
-/polyspermy

“Unfortunate daughter of faulty FATHER / PARENTS”

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COMPLETE MOLE

A single sperm fertilizes an


ENDODUPLICATION empty ovum, with
Empty endoduplication of the 23X
ovum 46XX
46xx haploid set of chromosomes,
giving rise to a homozygous
diploid complete mole.

23X
Complete Mole
(46XX diploid)
DIANDRY

Two sperms with two


Empty independent haploid sets of
ovum 46XX or chromosomes fertilize an
46XY empty ovum, producing a
dyspermic heterozygous
complete mole with either
23X 23X or Y
Complete Mole (46XX 46XX or 46XY karyotype.
or 46XY, diploid)

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Modified from Cheung, 1995
Generation of enucleated oocytes !!!

• is not clear,

• but one possible error is a


non-disjunction of all
chromosomes during
meiosis, with all
chromosomes ending up
in one of the polar bodie

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Imprinted genetics
• The chr 11p15.5 harbours several genes with a different
imprinting pattern

• p57kip2,
• IPL paternally imprinted or silenced
• H19

• IGF2
• KCNQIOT1 maternally imprinted.

• In a hydatidiform mole, the presence of paternally derived


chromosomes only leads to an abnormal expression pattern
of these imprinted genes.

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Chromosome – 11p15.5

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BIPARENTAL COMPLETE MOLE
(imprinting switch)

In exceptional cases ( 10 families have been reported) of histologically
typical complete hydatidiform mole, a biparental origin of the
chromosomes has been found (reviewed by Fisher et al., 2004b ).

• The interpretation is that the maternal chromosomes behave as if they


were of paternal origin.

• Genomic imprinting is a reversible process, whereby the imprint is


reset during gametogenesis according to the sex of the parent.

• During oogenesis, genes silenced on the paternal chromosome must be


reactivated, whereas genes active on the paternal chromosome must be
silenced, and vice versa for spermatogenesis

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• At the DNA level, the signal mediating genomic imprinting is
methylation of CpG residues in specific chromosomal regions

•In the normal situation, a differentially methylated region (DMR) in the


KCNQIOT1 gene becomes ---
-methylated during oogenesis
-demethylated during spermatogenesis
•In the paternal HM, all imprinted genes carry an exclusively paternal
imprinting or methylation pattern.
•In the biparental HM, methylation but not demethylation is defective in
oogenesis, leading to an abnormal methylation of maternally imprinted
genes such as KCNQIOT1.

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abnormal methylation of maternally imprinted genes such as KCNQIOT1.

FAULT

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WAY FORWARD THOUGHTS----
• Methylation depends on specific enzymes, DNA
methyltransferases (Dnmt) and these are therefore excellent
candidate genes for the disorder.
• However, so far, no mutations have been reported in these
genes (Hayward et al., 2003 ).
• Meanwhile, as an alternative means to identify the molecular
basis of this autosomal recessive disorder, linkage analysis has
been performed in families with the disorder.
• This has led to the identification of a relatively small region on
chromosome 19q (Moglabey et al., 1999 ; Hodges et al., 2003
• Mutation analysis of candidate genes in this region will
eventually lead to the identification of the underlying gene,
and the elucidation of the pathogenesis of the disorder.

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FOCAL HYDROPIC CHANGES OF DEFECTIVE FETUS WITH
PLACENTA HYDROPIC PLACENTA

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Partial mole
• The partial mole is caused by a triploidy,

• Triploidy is one of the most common chromosomal


anomalies, with an incidence of 10% in spontaneous
abortions (Hassold et al., 1980 )

• The majority of triploidies are sporadic, but a few


cases have been reported with recurrent triploidy

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Triploid origin-----

• Diandry-- Mostly following dispermic


fertilisation of an ovum. (Zaragoza et al.,
2000

• Digynae-- In few failure of meiosis I or II


in the oogenesis leads to Triploidy with 46
maternally derived chromosomes and 23
paternal (Zaragoza et al., 2000 ).

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PARTIAL MOLE (DIANDRY)

23Y 23X

23X
23X
23X 69XXY
23Y

23X
Partial Mole
(69XXY, or 69XXX,
Dyspermy or 69XYY triploid)
23X/23Y or
23X/23X

Fertilization of a normal 23X haploid ovum by two sperms, producing a


triploid partial mole with either 69XXY, 69XXX or 69XYY karyotype

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Modified from Cheung, 1995
PARTIAL MOLE (DIGYNAE)

2
3Y/
X
23X 23X
23X
69XXY
23X 23Y/
X
46XX
Partial Mole
(69XXY, or 69XXX,
DIPLOID OVUM triploid)

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Modified from Cheung, 1995
Triploidy features-----

-Diandry ---double paternal chromosome –


a focal molar placenta
the pregnancy rarely persists beyond 20 weeks.

- Digynae - double maternal chromosome –


the pregnancy may persist into the third trimester.
The placenta may be of normal
fetus demonstrates severe asymmetrical IUGR

✂ mild ventriculomegaly,
✂ micrognathia,
✂ cardiac abnormalities,
✂ myelomeningocoele,
✂ syndactyly,
✂ ‘hitch-hiker’
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deformity.
Mosaic triploidy
*Triploidies are almost lethal, some children carry a triploidy
in only part of their cells, with the remaining cells having the
normal 46 chromosomes. This is called a mosaic triploidy.

*The mosaicism may originate from the incorporation of a


second sperm pronucleus into one embryonic blastomere

*In others, a maternal origin was detected, through the fusion


of one of the (haploid) second polar bodies with an early
blastomere
*In one instance, the most likely explanation was chimaerism
with fusion of two separate zygotes developing into a single
individual

*Mosaic triploidy can be viable, depending on the percentage35


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of abnormal cells and their tissue distribution
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COMPLETE HYDATIFORM MOLE
CLINICAL FEATURES

Vaginal bleeding (anemia) 97%


Excessive uterine size 50%
Theco-lutein ovarian cysts 50%
Preeclampsia 27%
Hyperemesis 25%
Hyperthyroidism 7%
Trophoblastic embolization 2%
(respiratory distress)

NOTE – SOME ABNORMAL PRESENTATION ARE DUE TO HIGH LEVEL OF hCG


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THECA LEUTIN OVARIAN CYST

• Incidence - 20- 60 % (avg – 50 %)


• Size - > 6cm
• Bilateral
• Moltilocular
• Functional ~ secrets E2 & progesteron
corresponds with hCG level
• Regresses spontaneously after expulsion
• Very rarely undergo torsion

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PREECLAMPSIA
Incidence - ~ 27% of complete mole

If PIH is found < 20 wks of GA suspect HM

Provocating factors –

8. Very high hCG level


9. Excessive uterine size

- Convulsion is very rare

- Subsides dramaticaly after expulsion of mole


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HYPEREMESIS
• Aetiology ---

- high level of hCG


- excessive uterine size

-severe disturbance is infrequent


-subsides after the expulsion of mole

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HYPERTHYROIDISM
alfa subunit of hCG & TSH simulate molecularly
• High hCG ----- high level of free T3 & T4

Menifestations ----

• -supraventricular tachycardia
• Palpitation
• Goitre
• Increased sweating
• Heat intolarance
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Thyroid storm
Hyper thyroidism precipitate by –
Toximia
Infection
Surgery
Anaesthesia
ventricular Tachycardia
Menifestations -
Delirium , convulsion
Hyperthermia
Fibrillation
CVS collapse
Treatment ---- promt tr. With
- Beta blockers ,Anti thyroid medication
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TROPHOBLASTIC EMBOLISATION

• Incidence – 2% of mole
• Features of respiratory insufficiency ---
tachycardia, tachypnea, anxiety, confusion immediately
after the evacuation
• Reasons ---
6. embolisation of molar tissue to pulmonary vasculature
D/D --
• Cardiovascular complication of pre eclampsia
• Thyroid storm
• Massive fluid replacement

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PARTIAL MOLE

Way of encountering----

1- missed abortion & incomlete abortion


conceptus --- H/P & DNA analysis

2- Morphologic analysis of fetus & placenta

3- USG –
-- high suspicion in early trimester
--TIFA – anomaly suggesting triploidy /
Placental hydropic changes

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examination of products of conception

--All products of conception obtained after evacuation


(medical or surgical) should undergo histological examination
in order to exclude trophoblastic neoplasia.

--Ploidy status may help in distinguishing partial from


complete
moles.

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Diagnosis of partial mole (very early stage)

Presence of multiple soft markers

4. cystic spaces in the placenta


5. ratio of transverse to AP dimension of the gestation sac
of > 1.5

When there is diagnostic doubt about the possibility of a combined


molar pregnancy with a viable fetus then ultrasound examination
should be repeated before intervention.

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PARTIAL MOLE
FIRST TRIMESTER DIAGNOSIS

 Discrepancy between CRL and LMP

 Increased fetal nuchal translucency

 Increased ß HCG levels for gestational age

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PARTIAL MOLE - USG – 2nd trimester

More than 90% of partial moles are found in triploid fetuses.

Feto-placental ultrasound findings %

Fetal anatomic defects 92.9


Asymmetrical growth restriction 64.2
Placental molar changes 28.6
Amniotic fluid changes 47.1
Olygohydramnios 44.2
Polyhydramnios 2.9

Jauniaux E, Nicolaides KH: Placenta 1997, 18; 701-6


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Ultrasound abnormalities in triploid fetuses
Variables %
Malformed hands 52.3
Ventriculomegaly 36.9
Heart abnormalities 33.9
Micrognathia 26.2
Hyperechogenic bowel 15.4
Renal malformations 12.3
Increased nuchal thickness 12.3
Spina bifida 7.7
Talipes equinovarous 7.7
Dandy-Walker malformation 7.7
Collapsed stomach 7.7
Single umbilical artery 6.2
Omphalocele 6.2
Holoprosencephaly 3.1
Hydrops 3.1
Bilateral pleural effusion 3.1
Ascites 3.1
Diaphragmatic hernia 1.5
Kyphoscoliosis 1.5
Cleft lip and palate 1.5
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Jauniaux E, Nicolaides KH: Placenta 1997, 18; 701-6
Abnormal encountering of mole

GTD and Twin Pregnancy---


Incidence 1:22.000 – 1:100.000

Variants viable fetus with partial hydatiform mole

viable fetus with complete hydatiform mole

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GTD and Twin Pregnancy

1. If there is one viable fetus and the other pregnancy is molar, the
pregnancy could be allowed to proceed if the mother wishes,
following appropriate counselling.

2- The probability of achieving a viable baby is 40% and there is a


risk
of complications such as pulmonary embolism and pre-eclampsia.

3- There is no increased risk of developing persistent GTN after such


a twin pregnancy and outcome after chemotherapy is unaffected.

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COMPLETE HYDATIFORM MOLE AND COEXISTING VIABLE FETUS

Outcome !!!

Miscarriage 50%

Stillbirth <32 wks 30%

Preterm delivery <32 wks 30%

Pre-eclampsia > 50%

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SUMMARY -----MISTAKES & PENALTY

• UNFORTUNATE PENALTY TO A LADY FOR THE


PARTIAL OR COMPLETE ALLOGRAFT DUE TO A
SERIES OF MISTAKES OF FERTILISATION.

• PENALTY MAY BE SIMPLE TO LIFE THRETNING


RESULTING IN MORBIDITY & MORTALITY

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